Many pharmaceutical compositions are manufactured under sterile conditions.
In the case of “multi-dose” packaging of sterile compositions, it is required that the composition remains sterile after opening the packaging and during period of use. This is especially the case for ophthalmic eye drops which are applied topically directly on the surface of the eye. This eye drop should not, in any way, become a vehicle susceptible of carrying bacterial or fungal contamination into the eye. Consequently, after opening a multi-dose packaging, ophthalmic composition should remain sterile during the period of use i.e. about 15 days in most cases, and should therefore have sufficient preservative activity to comply with the preservation efficacy requirements of the US pharmacopeia (USP) and European pharmacopeia (Ph. Eur.) or analogous guidelines in other countries. A composition with a preservative activity should be understood, in the meaning of the present invention, as a composition in which there is few, if any, microbial or fungal proliferation and which satisfies the preservation efficacy requirements of pharmacopeias. In the meaning of this invention, a preservative activity is related to keeping the composition safe, sterile and clean, and is not related with any therapeutic effect. On the contrary, the term “antimicrobial activity” refers to a therapeutic effect of a composition when applied on the eye of a patient, in order to avoid or to eliminate the presence of germs in the eye.
One solution to prevent contamination of a composition after opening of a multi-dose container is to use a specific packaging system, including for example specific filters placed on the opening. This solution presents the drawback of being very expensive and not accepted by some and any health authorities.
Another solution to maintain a composition sterile after opening the packaging is to include preservative agents in the formulation, generally composed of cetrimide, cetylpyridinium chloride, polyquaternium, benzalkonium chloride, benzethonium chloride, benzododecinium or other classes of preservatives such as chlorobutanol, mercurial preservatives and parabens. However, these preservatives are known to be irritant and not well tolerated by patients, especially when used chronically. Consequently, in order to minimize harmful effects, there is a need to use less toxic preservatives and/or to use preservative agents at the lowest possible concentrations (i.e. the minimum amount required to obtain a preservative activity).
Less toxic preservatives may be for example purite, oxychloro complex or sodium perborate, that act by releasing oxygen in the environment of the microorganisms. However, these products present the drawback to be heat sensitive and therefore are not compatible with ophthalmic compositions that should be sterilized by heat or able to be kept in hot climate.
Therefore, there is also a need for new preserved ophthalmic compositions that do not induce adverse effect for the eyes linked to the presence of preservative agents, that may be easily sterilized and that are not heat sensitive.
Compositions that do not contain a preservative effective amount of a conventional preservative agents but are still preserved from microbial and/or fungal contaminations have been referred to in the art as being “preservative free” or “self-preserved” compositions (see for example U.S. Pat. No. 5,597,559 or U.S. Pat. No. 6,492,361).
The concept of self-preserved compositions was developed in prior patent applications, for example WO2008042619, WO200836847, WO200836855. Aqueous solutions described in these patent applications do not comprise conventional preservative agents. They are based on the use of zinc ions together with either (i) a limited concentration of anionic species or (ii) complexes of borate plus excipients (such as polyol or amino alcohol).
The use of boric acid to preserve aqueous solutions is described in specific concentrations only; indeed, boric acid concentrations to be used in order to obtain an antibacterial effect in a solution are quite high, i.e. more than 1.2% w/w. It was reported that a solution comprising 1.2% w/w of borate had some antimicrobial activity but that this concentration was not sufficient to meet the criteria for antimicrobial effectiveness given by USP (Houlsby R. D., Ghajar M. and Chavez G., Antimicrobial Agent and Chemotherapy, 1986, 29(5), 803-806).
In self-preserved solutions described in patent applications WO2008042619, WO200836847, WO200836855, the use of zinc ions or of excipients allows reducing the concentration of borate in the solution to obtain effective preservative activity in the meaning of USP: borate is used there in amounts ranging from 0.15% to 1% in weight of the total weight of the composition.
Patent application US2008089953 describes a composition containing tobramycin, an antibiotic, with a complex of borate and glycerol to enhance the preservative effect of tobramycin itself. A high quantity of borate (1%) is necessary to obtain a fully self-preserved composition.
Therefore, it was well admitted that boric acid is a rather weak preservative agent and that elevated concentrations of boric acid have to be used to obtain preserved compositions.
Literature reports cases of toxicity induced by boric acid on corneal cells.
Teranishi et al. showed that the concentration of 0.1% boric acid to be safe while 0.5% to 1% are toxic to corneal and epithelial cells (Teranishi S., Chikama T.-I., Kimura K. and Nishida T., XIX Biennial Meeting of the Internatioanl Society for Eye Research, Jul. 18-23, 2010, Montreal, Canada).
It was also reported that when boric acid is used in cleaning contact lenses solutions a strong corneal cytotoxicity can be observed (Tanti N. C., Jones L. and Gorbet M. B., Optometry and Vision Science, 2011, 88(4), 483-492; Gorbet M. B., Tanti N. C., Jones L. and Sheardown H., Molecular Vision, 2010, 16, 272-282).
Therefore, it is well admitted in the art that the use of boric acid in ophthalmic compositions may result in corneal toxicity after topical application when highly concentrated.
In the field of oil dispersions, especially ophthalmic oil-in-water emulsions, preservative agents commercially used are generally the same as the conventional ones used in ophthalmic solutions. Therefore, similar issues of irritation and side-effects are encountered.
As emulsions are very sensitive systems, especially relative to stability concerns, developing new preservative systems is very challenging. Moreover, it has been demonstrated that numerous commonly used preservative agents are neutralized in oil-in-water emulsions by inclusion in the oily phase (Sznitowska M., Janicki S., Dabrowska E. A. and Gajewska M., Eur. J. Pharm. Sci., 2002, 15(5), 489-95). Indeed, Sznitowska et al. investigated the distribution of different preservative agents between water phase and oily phase. They found that an important part of these preservative agents, even water-soluble ones, was found to be in oily phase. As a result, preservative efficacy was reduced relative to what may be expected with the total concentration of preservative used.
Surprisingly, the Applicant found that oil dispersions could be preserved and meet preservation efficacy requirements of pharmacopeias by using a very small amount of boric acid, said dispersions not encompassing any other preservative agent. Such dispersions were found to be safe for the eyes and not toxic to corneal cells. Without willing to be linked by a theory, the Applicant believes that it may be the fact that the eye drop composition is a dispersion, and not a solution, that may impact the effect of boric acid: amounts of boric acid used in the dispersions of the present invention are lower than the amounts described in the prior art to preserve solutions.
The Applicant found that (1) a solution encompassing a low concentration of boric acid, in absence of any other preservation system or agent, has no preservative activity and (2) on the contrary a dispersion of the invention encompassing a low concentration of boric acid, in absence of any other preservation system or agent, has a preservative activity.
This invention was quite surprising, as in the knowledge of the Applicant, nothing in the prior art disclose or suggest that using low amounts, i.e. non-toxic amounts of boric acid could, in absence of any other conventional preservative, lead to a self-preserved dispersion. Especially, the use of boric acid in ophthalmic oil-in-water emulsion in concentrations described therein is not disclosed or suggested by the prior art for manufacturing self-preserved emulsions or for manufacturing emulsions having a preservative activity.
Without willing to be linked by any theory, this unexpected phenomenon could be explained by a synergy between the oily phase of the oil dispersion and boric acid, said synergy resulting in a preservative activity. For this reason, boric acid will be referred to as a “preservation promoter” in the following description.
The Applicant also found that when the oil dispersion is positively charged, boric acid seems to have an even much stronger effect so that a lower concentration of boric acid is required for a cationic oil dispersion with comparison to a non-ionic oil dispersion.
Therefore, the present invention presents the advantage of providing a preserved oil dispersion comprising a low amount of boric acid, being free of conventional preservative agents and being of safe-use on the eye.